A bispecific antibody having a CD20-binding arm and a CD3-binding arm may provide the necessary crosstalk to augment antitumor activity. A third modality in such a bispecific antibody is the Fc domain. Modification of Fc binding properties has been found to augment the antitumor potency of a therapeutic antibody.
Binding of an immunoglobulin Fc domain to its receptor brings effector cells to sites of the bound antigen, resulting ultimately in a variety of signaling and immune responses. These various “effector functions”, such as CDC and ADCC, are the results of immunoglobulins of the G class (IgGs) forming a complex between the Fab domain of the IgG and a target antigen, whereas the Fc domain of the IgG binds to Fc receptors on effector cells. Some effector functions of IgG are independent of antigen binding and embody functions such as circulating serum levels and ability to transfer Ig across barriers. Other effector functions are considered essential for use in immunoglobulin therapies, such as cancer treatments. The ADCC mechanism in particular is considered to be one of the primary anti-tumor mechanisms of therapeutic antibodies already on the market such as rastuzumab (metastatic breast cancer) and rituximab (non-Hodgkin's lymphoma).
Current therapeutic strategies typically suggest that reduced effector functions (or reduced Fc gamma receptor binding) by modified Fc domains of antibodies may be useful for antibodies whose aim is to neutralize or inhibit the biological activity of an antigen (e.g. antibody blockers or antagonists), or activate or initiate downstream cellular signalling (e.g. antibody agonists).
However, the design of tumor targeting antibodies with reduced effector function is counterintuitive for tumor therapy, since it is expected that reduced cytotoxicity (i.e. ADCC and CDC) of target cells will not be efficacious to treat the disease, i.e. destroy tumor cells or inhibit tumor growth.
One strategy, described herein, utilizes differential Fc receptor binding combined with bispecific antigen binding to specifically target tumor markers as well as trigger tumor-specific T cell killing. The antibody's Fc domain is designed to carefully control Fc receptor binding to eliminate or reduce undesirable killing of cells like T cells, natural killer cells and macrophages bearing Fc receptors. A unique binding pattern with respect to Fc receptor interaction comprising FcγRII receptor binding interactions, but lacking FcγRI or FcγRIII interactions, is surprisingly beneficial for a tumor-targeting Ig therapy in the context of bispecific antibodies that bind both CD3 and CD20. Still, there is a need find better therapies that stimulate the immune system and are effective at tumor ablation, without causing excess cytokine release and toxicity to the patient.
Current bispecific therapies, such as BiTE® (Bi-specific T-cell engager) antibodies, are administered in minute doses however at frequent intervals. There is an unmet medical need for additional treatment options with tolerable dosing regimens for patients with CD20+ B-cell malignancies, especially those patients relapsing or progressing after initial therapy.